In the synthesis of pharmaceuticals, reductions in the amount of impurities are strongly required in view of enhancing safety of the pharmaceuticals that are final products. In particular, isomers that are by-products in the reaction steps conducted in preparing a pharmaceutical usually resemble each other in physical properties, so that the separation for purification is not easy. Therefore, isomers in the starting materials and intermediates produced by preceding steps may cause various side reactions in the subsequent reactions conducted in preparing the pharmaceutical, which results in a final product containing high contents of various side reaction products as impurities. Therefore, the isomer content of starting materials used for preparing a pharmaceutical is often strictly controlled in units of 0.1 wt. %.
Likewise for the production of 2-acylthiophene compounds that are useful as starting materials and intermediates for preparing pharmaceuticals and the like, a process of production with a low isomer content is similarly desired. Further, a process of production thereof without using solvent, in particular, organic solvent, is strongly desired from the viewpoint of environmental concerns and production costs.
Conventionally, various processes for producing 2-acylthiophene compounds in the absence of solvent are known. Examples of such known processes include a process comprising reacting thiophene and an acid anhydride using activated clay under reflux (J. Am. Chem. Soc., 69, 1014, (1947)) and a process comprising reacting thiophene and acetic anhydride using an ion exchange resin at 75° C. to 125° C. (U.S. Pat. No. 2,711,414).
However, products obtained by conventional processes for producing 2-acylthiophene compounds contain comparatively large amounts of by-product 3-isomers, i.e., have an isomer content of about 1 wt. % and furthermore, separation thereof is not easy. Therefore, when the compound is to be used as a starting material or an intermediate for preparing a pharmaceutical or the like, it has been necessary to perform purification using a multiple-plate distillation column, etc.
For example, in the production of 2-acetylthiophene, when distillation is performed during the post-production process to separate the 3-isomer to thereby purify the product, simple distillation is virtually ineffective and it is necessary to use a multiple-plate distillation column, etc. For example, even when a 50 theoretical plate distillation column is used in a distillation process for purification to obtain 2-acetylthiophene with a 3-isomer content of 0.5 wt. % from 2-acetylthiophene with a 3-isomer content of 0.9 wt. %, the purification yield was only about 70%. Therefore, also because it is not easy to separate the 3-isomer produced, a process of production with a low by-product 3-isomer content is desired.